title: HA-coated chitosan nanoparticles for CD44-mediated nucleic acid delivery.
abstract: CD44, the main receptor of hyaluronic acid (HA), is overexpressed in several pathological conditions and therefore can be seen as an interesting target for therapeutic intervention. Here, an approach using HA-coated chitosan (CS)-triphosphate (TPP) nanoparticles is investigated, using CS with different molecular weight (25 and 684 kDa), which influences HA presentation, and enzymatic and pH stability. In a study of nuclease stability, post-digestion of nanoparticles with chitosanase reveals that pDNA is at least partially degraded by DNAse; this may suggest that literature results overestimate the polyplex stability against nucleases. Using cells with a significantly different CD44 expression (RAW 264.7 macrophages-high levels; K562 leukemia cells-low levels; Kelly neuroblastoma cells-absent), the selectivity of CD44-mediated transfection is proven. Further, using luciferase pDNA and then later anti-luc siRNA, low MW CS-based nanoparticles show the best results despite a lower internalization efficiency; this effect is ascribed to a more efficient endosomal disruption and nucleic acid de-complexation.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Almalik
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Day
authors.forename: Nicola
authors.initials: N
authors.lastname: Tirelli
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry*; D004247:DNA / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D017930:Genes, Reporter; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry*; D020014:K562 Cells; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008970:Molecular Weight; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D010316:Particle Size; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D006820:Hyaluronic Acid; D004247:DNA; D048271:Chitosan; D008156:Luciferases
keywords: CD44; hyaluronic acid; macrophages; nanoparticles; receptor-mediated internalization